A Pharmacodynamic Study of Sirolimus and Metformin in Patients With Advanced Solid Tumors
- Conditions
- Breast NeoplasmsLung NeoplasmsCancer of LiverLymphomaCancer of Kidney
- Interventions
- Registration Number
- NCT02145559
- Lead Sponsor
- University of Chicago
- Brief Summary
Given the role of mTOR signaling and probable synergistic activity of combining sirolimus and metformin in patients with advanced solid tumors, the investigators hypothesize that:
1. The combination of metformin plus sirolimus will result in reduction of p4EBP1, p70S6K and pAKT more than sirolimus alone in peripheral blood T cells (PBTC).
2. The combination of metformin plus sirolimus will result in decreased levels of serum biomarkers including fasting insulin, C-peptide, glucose, triglycerides, LDH, IGF-1, IGF-1R, IGF-BP and leptin, but an increase in adiponectin in peripheral blood.
3. Expression of active forms of AMPK, mTOR, PI3K, PTEN loss, AKT, LKB1, P62, LC3, and/or ULK1 in the tumor tissue (original pathology) will be predictive of response to combination therapy. This will be an exploratory hypothesis for this study.
4. Sirolimus induced toxicity, especially hyperglycemia and hypertriglyceridemia, will be mitigated by combining sirolimus with metformin.
5. Metformin plus sirolimus will have promising anti-cancer activity and this activity will correlate with decreases in the above biomarkers. This will be an exploratory hypothesis for this study.
- Detailed Description
Objectives:
This is a descriptive study to evaluate the pharmacodynamic markers of dual sirolimus and metformin therapy.
Primary Objective:
i. To compare the change in the pharmacodynamic biomarker p70S6K in peripheral blood T cells with the combination of metformin XR and sirolimus to that with sirolimus alone.
Secondary Objectives:
i. To compare the changes in pharmacodynamic biomarkers p4EBP1 and pAKT in peripheral blood T cells with the combination of metformin XR and sirolimus to those with sirolimus alone.
ii. To assess the tolerability of the combination of metformin XR plus sirolimus at the selected doses.
iii. To compare fasting serum glucose and triglycerides on sirolimus before and after the addition of metformin XR.
Study Design:
This will be an open-label, randomized study in which all eligible patients with histologically-confirmed advanced solid tumors will be started on sirolimus (3 mg daily) alone for the first 7 days (lead-in period); cycle 1, days 1-8. Before starting the sirolimus the investigators will obtain previous pathology (if available) and collect blood lymphocytes for baseline testing of biomarkers as is shown in study calendar. The pharmacodynamic biomarkers will be collected again on cycle 1, day 8 to assess the effect of sirolimus alone on these biomarkers. In the previous study, the effect of sirolimus on p70S6K was observed within 48 hours of the first dose9. On day 8, patients will be randomized 1:1 to metformin XR (500 mg daily with the evening meal) or no metformin for two weeks (through day 21). On day 15, patients randomized to metformin XR will have their dose increased to 1000 mg daily if there is no grade ≥ 2 toxicity due to metformin XR. Patients who develop grade 2 toxicity due to metformin will be maintained on metformin XR 500 mg daily for the rest of the study, while patients who develop \> grade 2 toxicity will be taken off study. A repeat biomarkers evaluation will be done on cycle 1, day 22 to assess the effect of adding metformin on these pharmacodynamic biomarkers. From day 22 onwards, all patients will be on combination of sirolimus and metformin. Patients who were initially not randomized to metformin XR will begin taking it at 500 mg daily with an evening meal and titrated up to 1000 mg daily after one week, as above. Each cycle will be 4 weeks. CT scans will be obtained after every 2 cycles to assess the response by RECIST version 1.140. Metformin will be temporarily held on the day of CT scan and resumed 48 hours after CT scan. This is due to increased risk of lactic acidosis with iodinated contrast agent and is a standard procedure for contrast enhanced CT scan at the University of Chicago.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 24
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Metformin XR Metformin XR All eligible patients with histologically-confirmed advanced solid tumors will be started on sirolimus (3 mg daily) alone for the first 7 days. On day 8, patients will recieve metformin XR (500 mg daily with the evening meal)(through day 21). On day 15, patients randomized to metformin XR will have their dose increased to 1000 mg daily if there is no grade ≥ 2 toxicity due to metformin XR. Patients who develop grade 2 toxicity due to metformin will be maintained on metformin XR 500 mg daily for the rest of the study, while patients who develop \> grade 2 toxicity will be taken off study. From day 22 onwards, all patients will be on combination of sirolimus and metformin. Metformin XR Sirolimus All eligible patients with histologically-confirmed advanced solid tumors will be started on sirolimus (3 mg daily) alone for the first 7 days. On day 8, patients will recieve metformin XR (500 mg daily with the evening meal)(through day 21). On day 15, patients randomized to metformin XR will have their dose increased to 1000 mg daily if there is no grade ≥ 2 toxicity due to metformin XR. Patients who develop grade 2 toxicity due to metformin will be maintained on metformin XR 500 mg daily for the rest of the study, while patients who develop \> grade 2 toxicity will be taken off study. From day 22 onwards, all patients will be on combination of sirolimus and metformin. Delayed Metformin Delayed Metformin All eligible patients with histologically-confirmed advanced solid tumors will be started on sirolimus (3 mg daily) alone for the first 7 days. On day 8, patients will be randomized to receive no metformin for two weeks (through day 21). From day 22 onwards, all patients will be on combination of sirolimus and metformin. Patients who were initially not randomized to metformin XR will begin taking it at 500 mg daily with an evening meal and titrated up to 1000 mg daily after one week, as above. Each cycle will be 4 weeks. Delayed Metformin Sirolimus All eligible patients with histologically-confirmed advanced solid tumors will be started on sirolimus (3 mg daily) alone for the first 7 days. On day 8, patients will be randomized to receive no metformin for two weeks (through day 21). From day 22 onwards, all patients will be on combination of sirolimus and metformin. Patients who were initially not randomized to metformin XR will begin taking it at 500 mg daily with an evening meal and titrated up to 1000 mg daily after one week, as above. Each cycle will be 4 weeks.
- Primary Outcome Measures
Name Time Method Pharmacodynamic Biomarker p70S6K 28 days To compare the change in the pharmacodynamic biomarker p70S6K in peripheral blood T cells with the combination of metformin XR and sirolimus to that with sirolimus alone.
- Secondary Outcome Measures
Name Time Method Pharmacodynamic Biomarkers p4EBP1 and pAKT 28 days To compare the changes in pharmacodynamic biomarkers p4EBP1 and pAKT in peripheral blood T cells with the combination of metformin XR and sirolimus to those with sirolimus alone.
Tolerability - Full physical Exam 28 day cycles To assess the tolerability of the combination of metformin XR plus sirolimus at the selected doses a full history and physical exam will be conducted on days 1, 8, and 15.
Fasting Serum Glucose and Triglycerides 28 days To compare fasting serum glucose and triglycerides on sirolimus before and after the addition of metformin XR.
Trial Locations
- Locations (1)
University of Chicago
🇺🇸Chicago, Illinois, United States